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Animal Models of Metabolic Epilepsy and Epilepsy Associated Metabolic Dysfunction: a Systematic Review

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Animal Models of Metabolic Epilepsy and Epilepsy Associated Metabolic Dysfunction: a Systematic Review pharmaceuticals Review Animal Models of Metabolic Epilepsy and Epilepsy Associated Metabolic Dysfunction: A Systematic Review Uday Praful Kundap 1,2 , Yam Nath Paudel 1 and Mohd. Farooq Shaikh 2,* 1 Research Center of the University of Montreal Hospital Center (CRCHUM), Department of Neurosciences, Université de Montréal, Montréal, QC H2X 0A9, Canada; [email protected] (U.P.K.); [email protected] (Y.N.P.) 2 Neuropharmacology Research Strength, Jeffrey Cheah School of Medicine and Health Sciences, Monash University Malaysia, Selangor 47500, Malaysia * Correspondence: [email protected]; Tel.: +60-3-551-44-483 Received: 8 May 2020; Accepted: 23 May 2020; Published: 26 May 2020 Abstract: Epilepsy is a serious neurological disorder affecting around 70 million people globally and is characterized by spontaneous recurrent seizures. Recent evidence indicates that dysfunction in metabolic processes can lead to the alteration of neuronal and network excitability, thereby contributing to epileptogenesis. Developing a suitable animal model that can recapitulate all the clinical phenotypes of human metabolic epilepsy (ME) is crucial yet challenging. The specific environment of many symptoms as well as the primary state of the applicable neurobiology, genetics, and lack of valid biomarkers/diagnostic tests are the key factors that hinder the process of developing a suitable animal model. The present systematic review summarizes the current state of available animal models of metabolic dysfunction associated with epileptic disorders. A systematic search was performed by using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) model. A range of electronic databases, including google scholar, Springer, PubMed, ScienceDirect, and Scopus, were scanned between January 2000 and April 2020. Based on the selection criteria, 23 eligible articles were chosen and are discussed in the current review. Critical analysis of the selected literature delineated several available approaches that have been modeled into metabolic epilepsy and pointed out several drawbacks associated with the currently available models. The result describes available models of metabolic dysfunction associated with epileptic disorder, such as mitochondrial respiration deficits, Lafora disease (LD) model-altered glycogen metabolism, causing epilepsy, glucose transporter 1 (GLUT1) deficiency, adiponectin responsive seizures, phospholipid dysfunction, glutaric aciduria, mitochondrial disorders, pyruvate dehydrogenase (PDH) α-subunit gene (PDHA1), pyridoxine dependent epilepsy (PDE), BCL2-associated agonist of cell death (BAD), Kcna1 knock out (KO), and long noncoding RNAs (lncRNA) cancer susceptibility candidate 2 (lncRNA CASC2). Finally, the review highlights certain focus areas that may increase the possibilities of developing more suitable animal models and underscores the importance of the rationalization of animal models and evaluation methods for studying ME. The review also suggests the pressing need of developing precise robust animal models and evaluation methods for investigating ME. Keywords: metabolic epilepsy; animal model; mitochondrial dysfunction; metabolic genes; translational research 1. Introduction Metabolic abnormalities (ME) causing high brain activity are associated with an increased risk of epilepsy development in affected individuals. ME is caused by an array of toxic or metabolic Pharmaceuticals 2020, 13, 106; doi:10.3390/ph13060106 www.mdpi.com/journal/pharmaceuticals Pharmaceuticals 2020, 13, 106 2 of 35 diseases, such as mitochondrial dysfunction, alteration of intracellular osmolytes, accumulation of toxic substances, and a decrease of substrates that are crucial for internal membrane function or cellular metabolism [1]. All these factors combined result in a compromised efficacy to supply energy in the brain area, leading to excitability of the neuronal cells and producing epileptic seizures [2]. Moreover, the novelty of this research would be the study of how metabolic dysfunction can contribute to seizures and exacerbate related sequalae such as neuronal loss and related complications [3]. According to the International League Against Epilepsy (ILAE), ME is classified based on deficiency syndrome and disorder related to mitochondria or metabolism [4] (Figure1). Biotinidase deficiency or “Holocarboxylase synthetase deficiency” is a condition whereby the body is not able to utilize biotin properly [5]. The impairment of certain enzymes that are biotin dependent are categorized under a group of disorders known as “multiple carboxylase deficiencies” [6]. Cerebral folate deficiency (CFD) is a neurological syndrome associated with a low cerebrospinal fluid (CSF) concentration of 5-methyltetrahydrofolate (5MTHF) in the presence of normal peripheral folate metabolism [7]. Moreover, CFD might result in cerebellar ataxia, epilepsy, dyskinesia, psychomotor retardation, and spastic diplegia [8]. Disturbances in folate transport, which might be due to increased folate turnover within the central nervous system (CNS), may also lead to CFD [9]. In a majority of the CFD cases, the etiology remains elusive, however there is an increased understanding about the key role of mutation in folate receptor 1 (FOLR1) gene in CFD [10]. Further, folate receptor auto-antibodies suggests that CFD may be caused by the blocking of folic acid transport into CSF [8]. Creatine disorders are comprised of three defects, namely reduced creatine production in guanidinoacetate methyltransferase (GAMT), deficiencies of arginine glycine amidino transferase (AGAT), and decreased transport of creatine into the brain [11]. Epilepsy is associated with GAMT deficiency, which positively responds to the treatment which is substitutive with creatine monohydrate [12]. Folinic acid responsive seizures are diagnosed as an increase in monoamine metabolite in CSF, however, their genetic cause remains elusive [13]. Neonatal epileptic encephalopathy might be a cause of folinic acid responsive seizures and is treatable as the patients with this type of seizures respond well to pyridoxine therapy [14]. Mutations in solute carrier family 2 member1 (SLC2A1) gene are the cause of glucose transporter 1 (GLUT1) deficiency syndrome and results in the improper transportation of glucose into the brain [15]. A common inborn error of energy metabolism are a mitochondrial respiratory chain disorder. Tissues with a high energy requirement are usually affected by these disorders, which are frequently observed in childhood cerebral involvement and often leads to seizures [16]. Prominent myoclonic seizures are a common characteristic feature of numeral mitochondrial disorders together with Alpher’s syndrome, myoclonic epilepsy with ragged red fibers (MERRF), mitochondrial encephalopathy with lactic acidosis, and stroke-like episodes (MELAS) [17,18]. A group of inherited diseases where either peroxisomal function or one or more peroxisome biogenesis functions are disrupted are known as a peroxisomal disorder [19]. Pyridoxal 50-phosphate is the naturally active form of pyridoxine which is converted by a series of enzymes involving pyridoxamine phosphate oxidase (PNPO) [20]. Decreased levels of pyridoxal 50-phosphate in the CSF along with epilepsy are usually associated with PNPO [21]. Human ME constitutes a ranges of clinical, electrical, and behavioral demonstrations [22]. The selection or development of an animal model system is determined by several crucial factors, such as the type of epilepsy to be modelled, including the reason to be studied, acquaintance, and suitability, because of the large variety of pathological mechanisms involved in ME [23]. Pharmaceuticals 2020, 13, 106 3 of 35 Figure 1. Types of Metabolic Epilepsy. Pharmaceuticals 2020, 13, 106 4 of 35 Overall, 23 animal model studies that were mainly focused on different aspects of ME are reviewed in the current systematic review. Current study discusses the metabolic alterations studied in animal models that are associated with epilepsy. The major types of models are described with the use of animals to study metabolic disorders causing epilepsy or related disorders of CNS, and are further classified as follows: biotinidase and holocarboxylase synthase deficiency, CFD, creatine disorders, GLUT1 deficiency, folinic acid responsive seizures, mitochondrial disorders, peroxisomal disorders and pyridoxine-dependent epilepsy, and genetic knock out (KO) models (Figure2). Figure 2. Animal models of ME and epilepsy associated metabolic dysfunctions: This figure demonstrates the overall studies of animal model related to ME with different multi approach considered in the current review. Developing a suitable animal model that can recapitulate the clinical features of human ME is challenging as well as interesting [24]. The development of an animal model is complicated due to the specific nature of various symptoms, lack of validated biomarkers and objective diagnostic tests, the primary level of the specific neurobiology, and genetic factors [25]. Developing suitable animal models of ME will open a window of opportunity in this domain as well as strengthen our knowledge of the complex pathophysiology, mechanism, and therapy for the treatment of ME [26]. Herein, we systematically review the current state of several available pre-clinical models of ME and other related alterations. With respect to the reviewed literature, the authors consider the probable areas of interest that might intensify the likelihood of generating more valuable models,
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